In general, the present invention relates to small molecule inhibitors of the heat shock protein 90 (Hsp90) family of chaperone proteins, and pharmaceutical compositions thereof. The invention also features pharmaceutical compositions and kits that include the compounds and compositions of the invention. The invention further relates to the medical use of these compounds and compositions for the treatment of neurodegenerative diseases.
Hsp90 proteins are implicated in stabilizing protein conformations, maintaining the function of many cell-signaling proteins, and ATPase activity. Hsp90 activity is also required for the proper folding, stabilization, activation, and localization of oncoproteins involved in tumor progression (Pearl et al., Annu. Rev. Biochem. 75:271-94, 2006, and Luo et al., BMC Neuroscience 9(Suppl 2):57, 2008). The N-terminus ATP binding domain is responsible for the ATPase activity of this protein: this adenine nucleotide binding pocket is highly conserved among all Hsp90 proteins from bacteria to mammals but is not present in other chaperones (Grenert et al., J. Biol. Chem. 272:23843-50, 1997).
Crystallographic studies have shown that several Hsp90 inhibitors, such as the antitumor antibiotic geldanamycin, occupy the N-terminus ATP binding site (Roe et al., J. Med. Chem. 42:260-266, 1999), resulting in inhibition of Hsp90 ATPase activity and function. The use and therapeutic efficacy of geldanamycin and other Hsp90 inhibitors as antitumor agents relates to blocking multiple signaling pathways (see, e.g., Workman et al., Ann. N.Y. Acad. Sci. 1113:202-16, 2007, Chiosis, Expert Opin. Ther. Targets 10:37-50, 2006, and Xu et al., Clin. Cancer Res. 13:1625-9, 2007) and the increased level of Hsp90 activity in many tumors (Kamal et al., Nature 425:40710, 2003, and Mosseret et al., Oncogene 23:2907-2918, 2004).
Increased levels of Hsp90 have also been implicated in neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, and tauopathies (Dou et al., Proc. Natl. Acad. Sci. USA 100:721-726, 2003, and Ardley et al., Mol. Biol. Cell. 14:4541-4556, 2003). Tauopathies are neurodegenerative diseases characterized by tau protein abnormalities, which then result in the accumulation of hyperphosphorylated and aggregated tau protein (Murray et al., Biochem. Soc. Trans. 33:595-599, 2005, and Kosik et al., Biochim. Biophys. Acta. 1739:298-310, 2005). It has been proposed that hyperphosphorylated tau in Alzheimer's disease is a pathogenic process caused by aberrant activation of kinases, particularly cdk5 and GSK 133 (Dermaut et al., Trends Genet. 21:664-672, 2005, and Lau et al., Curr. Top. Med. Chem. 4:395-415, 2002). Other studies have shown that Hsp90 stabilizes p35, an activator of cdk5, leading to increased tau phosphorylation (Luo et al., Proc. Natl. Acad. Sci. USA 104:9511-9516, 2007 and Dickey et al., J. Clin. Invest. 117:648-658, 2007). It has also been shown that Hsp90 inhibition activates heat shock factor 1 (HSF1), which in turn increases the expression of Hsp70 (Ciechanover et al., Neuron 40:427-410, 2003,). Increased Hsp70 promotes tau solubility and binding to microtubules, inhibits protein aggregation, and enhances degradation.
Accordingly, inhibitors of Hsp90 represent beneficial therapeutics for the treatment of disorders such as cancer, neurodegenerative diseases, or viral infection.